Epidermolysis Bullosa Acquisita

Diagnosis

Indications for Testing

  • Presence of chronic blistering, erosive and/or crusting skin disease
  • More common diseases ruled out

Laboratory Testing

  • Initial serum testing – test for pemphigus, pemphigoid, and endomysial antibodies, or epithelial skin antibodies
    • Broad screening recommended unless a specific immunobullous skin disease type is suspected
    • Serologic diagnosis – positive in 90% of cases
  • Pemphigoid panel – IgG basement membrane zone (BMZ) antibodies positive titer >1:10 with dermal pattern is diagnostic for epidermolysis bullosa acquisita (EBA)
    • Collagen type VII antibody IgG by ELISA

Histology

  • Immunohistology
    • Perilesional skin biopsy for direct immunofluorescence (DIF) – gold standard for diagnosis
      • Linear BMZ deposition of IgG and/or third component of complement (C3) along BMZ of perilesional tissue
    • Dermal pattern localization of serum IgG BMZ antibodies on human split skin substrate by indirect immunofluorescence

      • Characteristically found in EBA
      • Also found in
        • Subset of bullous systemic lupus erythematosus
        • Two subsets of pemphigoid
          • Anti-laminin 332 pemphigoid
          • Anti-laminin γ1 pemphigoid
      • Collagen VII IgG antibodies not increased
        • Up to one third of laminin 332 antibody pemphigoid cases with dermal pattern BMZ antibody staining have underlying malignancy or will be diagnosed with malignancy in a few months
        • Further clinical evaluation should be pursued as indicated
      • Collagen VII antibodies increased
        • Unknown whether patients also may have laminin 332 antibodies
        • The association with malignancy and dermal pattern BMZ antibody staining should be considered

Differential Diagnosis

Monitoring

  • Collagen type VII IgG antibody and epithelial skin antibody OR

  • Collagen type VII IgG antibody and IgG BMZ antibodies

Clinical Background

Epidermolysis bullosa acquisita (EBA) is a rare, chronic autoimmune blistering disease.

Epidemiology

  • Incidence – 25/100,000
  • Age
    • Peak onset in 40s for acquired form
    • Infancy for inherited form
  • Sex – M:F, equal
  • Genetics
    • Mutation present in inherited forms
    • Multiple mutations may be responsible including KRT5, KRT14, LAM 3, LAMB3, LAMC2, COL17A2

Pathophysiology

  • Subepidermal blister formation characterized by autoantibodies to structural components of skin and adjacent mucous membranes (specifically collagen VII)
  • Collagen VII – component of anchoring fibrils within epithelial basement membrane zone (BMZ) (skin and mucous membranes)
    • Patients with EBA characteristically develop IgG antibodies to collagen VII
    • Major epitopes for EBA antibody reactivity reside in non-collagenous amino-terminal domain (NC1)
    • Minor epitopes reside in non-collagenous carboxy-terminal domain (NC2) of the three identical alpha chains that comprise collagen VII

Clinical Presentation

  • Acquired EBA
    • Four forms – classical, inflammatory, cicatricial pemphigoid-like, Brunsting-Perry pemphigoid-like
      • Classical variant
        • Mechanobullous – slight trauma elicits blistering and erosions; typically on extensor surfaces of elbows, knees, hands, feet
        • Non-inflammatory
        • Healing of lesions results in atrophyimilia (inclusions cysts), scars and pigmentation
      • Inflammatory variant
        • Resembles pemphigoid
        • Tense blistering on urticarial base
      • Cicatricial pemphigoid-like variant
        • Mucous membranes affected
        • Blistering lesions that scar
      • Brunsting-Perry pemphigoid-like variant
        • Head and neck involvement
        • Minimal mucosal disease
        • Scarring after blistering lesions
  • Inherited EBA
    • Four forms – epidermolysis bullosa (EB) simplex, junctional EB, dystrophic EB, Kindler syndrome

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Cutaneous Direct Immunofluorescence, Biopsy 0092572
Method: Direct Immunofluorescence
(Direct Fluorescent Antibody Stain)

Order concurrently with serum antibody testing and fixed tissue histopathology for assessment of patient with pruritic, urticarial, blistering and/or erosive disorders, including possible pemphigoid and pemphigoid variants, pemphigus and pemphigus subtypes, dermatitis herpetiformis, epidermolysis bullous acquisita, porphyria, and pseudoporphyria

Order concurrently with fixed tissue histopathology for assessment of patient with inflammatory, immune-mediated cutaneous disease, including possible lupus and lupus variants, vasculitis, drug reactions, lichen planus and lichenoid reactions

For skin involvement, biopsy perilesional skin

For mucous membrane involvement, biopsy nonlesional mucosa

See Immunobullous Skin Diseases Testing algorithm

May be inaccurate if tissue not taken from correct perilesional location (attached/intact epithelium or epidermis needed)

Not possible to reliably distinguish pemphigoid from epidermolysis bullosa acquisita or to distinguish pemphigus subtypes based on direct immunofluorescence (DIF); concurrent serum testing needed

Tissue must be submitted in Michel’s or Zeus medium; this test cannot be performed on formalin-fixed tissue

Initial concurrent and repeat serum testing with pemphigoid panel is the most sensitive for diagnosis, for determining antibody profiles, and for following disease activity

Patients with indeterminate results should have repeat DIF biopsy

Patients with changing clinical features should have repeat DIF biopsy because antibody profiles may change over time

Pemphigoid Antibody Panel - Epithelial Basement Membrane Zone Antibodies, IgG and IgA, BP180 and BP230 Antibodies, IgG 0092001
Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Preferred antibody panel for initial diagnostic assessment and disease monitoring in pemphigoid, epidermolysis bullosa acquisita, and linear IgA bullous dermatosis

Panel components include IgG and IgA epithelial BMZ antibodies and IgG bullous pemphigoid BP180 & 230 antigens

To order individual component tests, refer to antibody testing for IgG BMZ, IgA BMZ, and/or IgG bullous pemphigoid BP180 & 230 antigens

To screen for pemphigoid along with other possible immunobullous diseases, order concurrently with the pemphigus antibody panel  IgG collagen type VII antibody, AND perilesional skin biopsy for direct immunofluorescence

Concurrent perilesional skin biopsy for DIF is important for diagnosis because of increased sensitivity (85-100% of pemphigus, pemphigoid, linear IgA disease, epidermolysis bullosa acquisita, and dermatitis herpetiformis cases are positive)

See Immunobullous Skin Diseases Testing algorithm

Clinical correlation necessary because the incidence of false positives, although rare, increases with age

Because of clinical overlap among immunobullous diseases and similar names, pemphigoid testing may be confused with pemphigus testing and inadvertently misordered

Use pemphigoid panel or epithelial BMZ IgG antibody test to monitor EBA disease activity and response to therapy

Repeat pemphigoid panel or epithelial BMZ IgG antibody test for indeterminate results and/or continuing clinical consideration of EBA

Collagen Type VII Antibody IgG by ELISA  2010905
Method: Enzyme-Linked Immunosorbent Assay

For initial diagnosis and disease monitoring of epidermolysis bullosa acquisita

To further evaluate IgG BMZ antibodies, consider ordering with IgG antibody testing for epithelial BMZ and bullous pemphigoid (BP180 & 230) antigens

Consider other types of BMZ antibody-associated disease testing (ie, IgA epithelial BMZ and herpes gestationis factor)

To discriminate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease, order concurrently with testing for epithelial cell surface antibody or refer to antibody panel tests for pemphigoid and pemphigus

See Immunobullous Skin Diseases Testing algorithm

May not be positive in all patients with EBA, including those with antibodies to other epitopes in collagen VII than those expressed in ELISA

May also be positive in patients with bullous lupus erythematosus, inflammatory bowel disease, and Crohn disease

Patients with EBA may develop antibodies to other basement membrane components

Use with pemphigoid panel or epithelial IgG BMZ antibodies to follow disease activity in EBA

Repeat test for indeterminate results and/or continuing clinical consideration of EBA

Pemphigus Antibody Panel - Epithelial Cell Surface Antibodies and Desmoglein 1 and Desmoglein 3 Antibodies, IgG 0090650
Method: Enzyme-Linked Immunosorbent Assay/Indirect Fluorescent Antibody

Preferred panel for initial assessment and disease monitoring in IgG-variant pemphigus

Panel components include antibody testing for IgG epithelial cell surface and IgG desmoglein 1 and 3; to order individual component tests, refer to epithelial skin antibody and/or desmoglein 1 and 3 antibodies in pemphigus, IgG

To screen for pemphigus along with other possible immunobullous diseases, order concurrently with antibody panel test for pemphigoid, IgG collagen type VII antibody, AND perilesional skin biopsy for direct immunofluorescence

Concurrent perilesional skin biopsy for DIF is important for diagnosis because of increased sensitivity (85-100% of pemphigus, pemphigoid, linear IgA disease, epidermolysis bullosa acquisita, and dermatitis herpetiformis cases are positive)

See Immunobullous Skin Diseases Testing algorithm

Use pemphigus panel to monitor pemphigus disease activity; use relevant tests to monitor other immunobullous disease activity

Repeat pemphigus panel for indeterminate results and/or continuing clinical consideration of immunobullous disease

 
Tissue Transglutaminase (tTG) Antibody, IgA with Reflex to Endomysial Antibody, IgA by IFA 0050734
Method: Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Use along with pemphigoid and pemphigus panel tests and epidermal transglutaminase antibody, IgA, or use with epithelial skin antibody and epidermal transglutaminase antibody, IgA testing to initially diagnose and discriminate among the immunobullous skin diseases in patients suspected or known to have any type of immunobullous disease

Reflex pattern – if tTG IgA is ≥20 units, then EMA IgA by IFA testing will be added

See Immunobullous Skin Diseases Testing algorithm

Does not detect IgG or IgA BMZ or cell surface antibodies that characterize immunobullous diseases other than dermatitis herpetiformis

Use tissue transglutaminase (tTG) antibody, IgA with reflex to endomysial antibody, IgA by IFA for initial diagnosis of dermatitis herpetiformis and to follow disease activity in dermatitis herpetiformis; use relevant tests to monitor other immunobullous disease activity

Repeat test for indeterminate results and/or continuing clinical consideration of immunobullous disease

Epithelial Skin Antibody 0090299
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

General screen for immunobullous diseases

Test includes IgG and IgA BMZ antibodies (pemphigoid, epidermolysis bullosa acquisita, linear IgA disease) and IgG and IgA cell surface antibodies (IgG and IgA pemphigus subtypes)

Consider ordering concurrently with IgG bullous pemphigoid (BP180 & 230) antigens for suspected pemphigoid and/or IgG desmoglein 1 and 3 antibodies for suspected pemphigus

For more sensitive and specific testing for pemphigoid or pemphigus, refer to antibody panels for pemphigus or pemphigoid

See Immunobullous Skin Diseases Testing algorithm

Does not include testing for antibodies to target pemphigoid antigens, BP180 and BP230, or to target pemphigus antigens desmoglein 1 and 3 which may be more sensitive diagnostic markers in some cases (levels correlate with disease activity)

Although helpful in screening for immunobullous disease, test is not as sensitive as combination of pemphigus and pemphigoid panels

Use epithelial skin antibody test or both pemphigoid and pemphigus panels to follow patients with changing clinical features because antibody profiles may change over time
Epithelial Basement Membrane Zone Antibody IgG 0092056
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

Monitor disease in patient with pemphigoid or epidermolysis bullosa acquisita who has positive IgG BMZ antibodies by indirect immunofluorescence, either epidermal (roof) pattern or dermal (floor) pattern, on split skin substrate

Consider ordering concurrently with IgG antibody testing for bullous pemphigoid (BP180 & 230) antigens and/or collagen type VII

May use to screen for pemphigoid and other immunobullous diseases; however, this test has decreased sensitivity and specificity when compared to the panel tests for pemphigus antibodies or pemphigoid antibodies and will not detect IgA BMZ antibodies

See Immunobullous Skin Diseases Testing algorithm

Clinical correlation necessary because the incidence of false positives, although rare, increases with age

This test does NOT detect IgA BMZ antibodies; linear IgA disease and dermatitis herpetiformis will NOT be detected

Use epithelial BMZ IgG antibodies test to follow patients with EBA

Repeat epithelial basement membrane zone IgG antibodies test for indeterminate results and/or continuing clinical consideration of EBA